May 2015

Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial

Arthritis Res Ther. 2015 Apr 6;17(1):95.

Mean increases from baseline in patient serum creatinine (SCr) levels have been observed in the clinical development programme for the JAK inhibitor tofacitinib. These increases predominantly occurred within the first three months, and reversed with tofacitinib withdrawal.

This phase 1, randomised, placebo-controlled, parallel-group, 2-period study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib, relative to placebo, in 148 patients with active RA. Result...

Keywords:

Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme

Ann Rheum Dis. 2015 Apr 22. pii: annrheumdis-2014-205847. doi: 10.1136/annrheumdis-2014-205847. [Epub ahead of print]

The developments of certain malignancies associated with chronic inflammatory diseases such as RA is known to occur to a greater extent than that of the general population. It is also know that certain RA treatments can affect malignancy rates. As such, newer immunomodulatory agents, such as the JAK inhibitor tofacitinib, are closely monitored for safety events of special interest, including malignancies.

This paper analyses pooled malignancy data from the tofacitinib RA clinical develop...

Keywords:

April 2015

Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: Results of a phase III study

Arthritis Rheumatol. Vol. 67, No. 6, June 2015, pp 1424–1437

Biologic DMARDs targeting TNF-alpha, IL-1, T-cell co-stimulatory blockade, B-cell depletion, and IL-6R, as well as the newer JAK inhibitors have greatly improved clinical outcomes in RA. However, not all patients respond to current biologic or small molecule DMARDs.

Sarilumab is a fully human anti-IL-6Rα mAb that binds membrane-bound and soluble human IL-6R with high affinity, blocking cis and trans IL-6-mediated signalling. This study (MOBILITY) is the first randomised, double-blin...

Keywords:

The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis

Ann Rheum Dis. 2015 Mar 20. pii: annrheumdis-2014-207191. doi: 10.1136/annrheumdis-2014-207191. [Epub ahead of print]

The increased risk of serious infection among RA patients means vaccinations against pneumococcus and influenza are recommended in this group of patients. Studies evaluating immune response to these vaccines in conjunction with DMARD therapy can provide clinicians with important information relating to things such as timing of vaccination.

This study aimed to assess the effect of tofacitinib on vaccine responses to PPSV-23 and the trivalent seasonal influenza vaccine in those whom tofacit...

Keywords:

March 2015

A Randomized, Double-Blind, Placebo-Controlled, Twelve-Week, Dose-Ranging Study of Decernotinib, an Oral Selective JAK-3 Inhibitor, as Monotherapy in Patients With Active Rheumatoid Arthritis

Arthritis Rheumatol. 2015;67(2):334–343.

Decernotinib (VX-509; Vertex Pharmaceuticals Incorporated) is a JAK 3 inhibitor currently under investigation for its potential use in the treatment of RA. The potency and selectivity profiles of this oral compound have already been established in previous trials, so this study aimed to establish the efficacy and safety profiles of the drug, in RA patients who have had an inadequate response to at least one DMARD.

Four doses; 25 mg, 50 mg, 100 mg and 150 mg, were evaluated in this placebo...

Keywords:

January 2015

Potential Mechanisms Leading to the Abnormal Lipid Profile in Patients With Rheumatoid Arthritis Versus Healthy Volunteers and Reversal by Tofacitinib

Arthritis Rheumatol. 2015;67(3):616-25.

Active RA is associated with changes in both high- and low-density lipoprotein cholesterol as well as changes in the level and function of several HDL-associated proteins, yet the pathways and mechanisms involved with systemic inflammation altered lipid metabolism have not been determined. In addition, treatments for active RA are known to modify lipid metabolism, such as increasing circulating cholesterol levels. In the clinical development programme, a proportion of tofacitinib-treated patien...

Keywords:

Efficacy and Safety of Tofacitinib as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis: A 12-Week, Randomized, Phase 2 Study

Mod Rheumatol. 2014 Dec 11:1–25. [Epub ahead of print]

In Japan, the biologic DMARDs infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, as well as tocilizumab and abatacept are approved for use in patients with active RA and an inadequate response to existing therapies. However, not all patients respond to these therapies adequately, creating an unmet need for therapeutic options with alternative mechanisms of action.

The oral JAK inhibitor tofacitinib has demonstrated efficacy as monotherapy or in combination with DMARDs ...

Keywords:

The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers

Mod J Clin Pharmacol. 2014 Dec;54(12):1354-61. doi: 10.1002/jcph.354.

Current biologic therapies for RA, such as biologic cytokine inhibitors, which selectively target inflammatory molecules with an exquisite degree of specificity, are not clinically effective in all patients with rheumatoid arthritis. As such, there remains an unmet clinical need for more effective and better tolerated therapies. Baricitinib (LY3009104, also previously known as INCB028050) is a potent and selective small molecule inhibitor of JAK1/2, which play an important role in cytokine signa...

Keywords:

December 2014

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate

Ann Rheum Dis. 2015;74(2):333–340

Recent innovations in the treatment of RA have focused on the use of small molecules to inhibit intracellular kinases such as the JAK family. Baricitinib (LY3009104, formerly INCB028050) is an orally administered, potent, selective and reversible inhibitor of JAK1 and JAK2, which has shown anti-inflammatory effects, as well as preservation of cartilage and bone, in preclinical rodent studies.

This phase IIb study was designed to investigate multiple doses and dosing regimens of baricitin...

Keywords:

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels

Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]

Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...

Keywords: